Synthesis of α-Branched Amines by Three- and Four-Component C–H Functionalization Employing a Readily Diversifiable Hydrazone Directing Group

Abstract

Efficient syntheses of α-branched amines by three- and four-component C–H functionalization employing a diversifiable hydrazone directing group have been developed. The hydrazone in the α-branched amine products has been readily converted to multiple desirable functionalities such as a nitrile, a carboxylic acid, alkenes, and heterocycles using diverse heterolytic chemistry and homolytic transition metal- or photoredox-catalyzed processes. This study represents the first example of a four-component C–H functionalization reaction.

Graphical Abstract

Recently, we and others have reported on a three-component strategy for transition metal-catalyzed C–H activation and sequential addition to π-bonds and various electrophiles as a powerful approach for accessing molecular complexity (Scheme 1a).^1–3 As illustrated for the three-component synthesis of α-branched amines, which are present in an extensive number of approved drugs and drug candidates,⁴ a directing group such as an amide, ketoxime or a 5- or 6-membered nitrogen heteroaromatic is necessary to enable successful three-component coupling (Scheme 1b).^1e,g

Scheme 1.

Multicomponent C–H Functionalization

It would be highly desirable to utilize an easily introduced directing group that could later be elaborated into a wide range of different functionalities.⁵ We considered the hydrazone as a suitable directing group for this purpose. Hydrazones are easily synthesized in excellent yield by the condensation of a hydrazine and an aldehyde, of which enormous numbers are commercially available. Notably, hydrazones benefit from a very rich chemistry for their efficient conversion to diverse and useful structures under mild reaction conditions. In addition, hydrazones have already been demonstrated to direct transition metal-catalyzed ortho metalation in a limited number of contexts.^6,7

Herein, we report the Rh(III)-catalyzed synthesis of α-branched amines by three-component coupling of N,N-dialkyl hydrazones derived from aldehydes, terminal alkenes, and dioxazolones (Scheme 1c) as well as four-component coupling with hydrazones generated in situ from commercially available aldehydes and hydrazines (Scheme 1d). To our knowledge, this study represents the first reported example of a transition-metal catalyzed four-component C–H functionalization reaction.

Broad scope was observed for aliphatic alkenes and styrenes, dioxazolone amidating reagents with different electronic and steric properties, and different aromatic aldehyde and N,N-dialkyl hydrazine combinations. Importantly, the hydrazone in the α-branched amine products was readily converted to multiple desirable functionalities such as a nitrile, a carboxylic acid, alkenes, and heterocycles using a variety of different types of heterolytic chemistry and single-electron reactions mediated by either transition metal or photoredox catalysis.

The optimal reaction conditions for the three-component reaction were first determined, including the evaluation of catalysts, additives and solvents (see Table S1 in the SI). While previous three-component amidations were performed in aprotic solvents,^1e–h hexafluoroisopropanol (HFIP) was found to be the preferred solvent for this transformation.

We next evaluated the scope of the alkene coupling partner (Scheme 2). The standard styrene coupling partner (4a) provided product in high yield. Many alkyl (4b-4f) and aromatic (4a, 4g-4k) terminal alkenes were effective coupling partners. Alkyl alkenes included allylbenzene (4b), 1-hexene (4c), β-branched 4-methylpentene (4d), and the more sterically demanding vinyl cyclohexane (4e), provided products in good to excellent yields. The gaseous feedstock ethylene, which provides access to α-methyl amines commonly found in drug structures, was also an effective coupling partner (4f). A variety of styrenyl coupling partners containing both electron withdrawing (4g-4i) and donating (4j) functionality provided product in excellent yield. Halogen (4g-4h) and boronic ester (4k) substituents at all arene positions could be introduced to provide useful functional handles for late-stage elaboration.

Scheme 2. Three-Component Reaction Alkene Scope.

^aConditions: 0.20 mmol of 1a, 0.40 mmol of 2, 0.22 mmol of 3a. Isolated yields of products after purification by chromatography are reported. ^b0.80 mmol of 2e.

The dioxazolones displayed a wide scope, leading to both aliphatic (4l-4n) and aromatic (4a, 4o-4r) amide products (Scheme 3). Acetamido (4l), isopropyl (4m), and n-heptyl (4n) amides were all obtained in good yields. A variety of aromatic dioxazolones including those with electron withdrawing (4o-4q) and donating (4r) groups could also be employed. The scalability of this method was demonstrated by preparation of 4l in good yield on the 1.0 mmol scale, employing half the standard catalyst loading.

Scheme 3. Three-Component Reaction Dioxazolone and Hydrazone Scope.

^aConditions: 0.20 mmol of 1, 0.40 mmol of 2a, 0.22 mmol of 3. Isolated yields of products after purification by chromatography are reported. ^bReaction performed on a 1.0 mmol scale in the hydrazone with 2.5 mol % of catalyst. ^c0.80 mmol of 2a.^dReaction performed with 0.40 mmol of 1d, 0.40 mmol of 2a, and 0.20 mmol of 3a at 20 °C for 40 h.

Additionally, this chemistry was effective for different N,N-dialkyl hydrazone substrates as demonstrated for morpholino (4s-4u) and dimethyl (4v) hydrazones (Scheme 3). The aryl group containing the C–H bond could also be modified; a blocking methyl group (employed to prohibit multicomponent over-functionalization) could be used at either the meta- (4a-4r) or ortho- (4s) positions relative to the hydrazone. Additionally, a meta-iodide group (4t) could be employed as a blocking group in good yield and with high regioselectivity. When no blocking group was employed, the reaction conditions were modified to reduce competing over-amidation products. Here, the dioxazolone was used as the limiting reagent, and the three-component reaction was achieved in moderate but synthetically useful yield (4u).

Although the hydrazone C–H bond reactants 1 can be readily prepared in near quantitative yields from vast numbers of commercially available aldehydes, their preparation adds a step to the overall synthesis of the α-branched amine products 4. We envisioned that the preparation of α-branched amines 4 in a single step from the corresponding aldehyde might be possible by in situ generation of the hydrazone via a four-component process (Scheme 4). In practice, formation of the hydrazone occurred quickly, likely catalyzed by the acidic HFIP solvent, to enable subsequent coupling to the alkene and dioxazolone coupling partners. We were gratified to find that the four-component reaction worked comparably to, and in some cases, better than, the corresponding three-component reaction. We demonstrate robust reactivity while maintaining diversity in the aldehyde (4a, 4s, 4u), hydrazine (4a, 4v), alkene (4a, 4d, 4f, 4g), and dioxazolone (4a, 4l, 4m) coupling partners. These examples represent the first transition-metal catalyzed one-pot four-component C–H functionalization reaction.

Scheme 4. Four-Component Reaction Scope.

^aConditions: 0.20 mmol of 5, 0.24 mmol of 6, 0.60 mmol of 2, 0.30 mmol of 3. Isolated yields of products after purification by chromatography are reported. ^bReaction performed with 0.44 mmol of 5c, 0.52 mmol of 6a, 0.65 mmol of 2a, 0.22 mmol of 3a at 20 °C for 40 h.

After establishing scope for this reaction, we were eager to explore the conversion of the hydrazone in α-branched amine products 4 to other useful functionalities (Scheme 5). Treatment of hydrazone 4l with the mild oxidant magnesium monoperoxyphthalate (MMPP) provided nitrile 7a in excellent yield.^6d Oxidative ozonolysis provided carboxylic acid 7b from the hydrazone in a one-pot procedure.⁸ Conversely, when the hydrazone was placed under reductive ozonolytic conditions, the aldehyde formed readily but nucleophilic attack by the nearby amide converted it to the cyclic hemiaminal, which proved to be a highly versatile intermediate. This hemiaminal intermediate retained aldehyde reactivity and could be converted in situ to alkene products via one-pot Wittig olefinations. Reaction with a stabilized ylide provided the (E)-α,β-unsaturated ester 7c while the unstabilized methyl phosphonium ylide gave styrene 7d. Treatment of the hemiaminal with boron trifluoride etherate and either triethylsilane or allyl(trimethyl)silane provided the isoindoline 7e and the allyl substituted isoindoline 7f, respectively.⁹ Isoindoline 7f was formed as a single diastereomer with the relative stereochemistry rigorously determined through X-ray crystallographic analysis (see Supporting Information).

Scheme 5. Diversification of Multicomponent Product 4l.

^aMMPP, MeOH. ^bO₃, NaClO₂, MeCN/H₂O. ^cO₃/DMS, EtOH, then ethyl 2-(triphenyl-λ⁵-phosphaneylidene)acetate. ^dO₃/DMS, CH₂Cl₂, then KHMDS, methyltriphenylphosphonium bromide. ^eO₃/DMS, MeOH, then BF₃•OEt₂, triethylsilane. ^fO₃/DMS, MeOH, then BF₃•OEt₂, allyl(trimethyl)silane. ^gTMSN₃, PhI(OAc)₂, Cu(OAc)₂, K₂CO₃, MeCN. ^hDiethyl bromomalonate, NaHCO₃, [Ir(ppy)₂(dtbbpy)][PF₆], MeCN, Blue LED.

In addition to heterolytic chemistry, we found that the hydrazone could also be converted to additional functional groups using homolytic chemistry. The hydrazone could be converted to the morpholine-substituted tetrazole 7g by employing Cu(II)-catalyzed annulative radical chemistry that activated the hydrazoyl position by SET.¹⁰ Moreover, under photoredox conditions, the drug-relevant bicyclic pyrazole 7h could also be prepared.¹¹ This interesting annulative transformation has primarily been reported for tetrahydroisoquinoline-derived hydrazones.¹² These results suggest that the hydrazone directing group should be an effective substrate for additional radical processes.¹³

The proposed mechanism of the four-component transformation begins with initial condensation of the hydrazine and aldehyde to form the hydrazone directing group (Scheme 6). This process is likely facilitated by the relatively acidic HFIP solvent. The active cationic Rh(III) catalyst then undergoes concerted metalation deprotonation to form rhodacycle I. Next, migratory insertion of the alkene forms the seven-membered rhodacycle II, which is known to undergo a syn-β-hydride elimination followed by a syn-hydride reinsertion at the other carbon position to give the more stable six-membered rhodacycle IV.^1e At this point, the dioxazolone adds into the Rh–C bond via a nitrene insertion process to form V, which upon protodemetalation furnishes the product VI and regenerates the active catalyst.

Scheme 6.

Proposed Mechanism for the Four-Component Transformation.

In summary, we have developed modular three- and four-component syntheses of α-branched amines employing a highly diversifiable hydrazone directing group. We demonstrate the effective elaboration of these hydrazones into useful functionalities including a nitrile, a carboxylic acid, alkenes, and various heterocycles via both heterolytic and homolytic radical and photoredox chemistries. This first example of a four-component C–H functionalization reaction enables the rapid construction of a complex branched amine motif while simultaneously introducing a handle for convenient elaboration to a variety of useful functionalities.